5alpha, 16alpha, 17alpha-trihydroxy-6beta-halopregnane-3, 20-bisethylene ketals



United States Patent ()fiFice 3,341,525 Patented Sept. 12, 1967 3,341,525 50,16a,17oc-TRlHYDROXY-6B-HALOPREGNANE- 3,20-BISETHYLENE KETALS Josef Fried, Princeton, N.J., assignor, by mesne assignmerits, to E. R. Squibb & Sons, Inc., New York, N.

a corporation of Delaware No Drawing. Filed Dec. 16, 1959, Ser. No. 859,840

2 Claims. (Cl. 260-23955) This invention relates to, and has for its object the provision of a method for preparing physiologically active steroids, and to the physiologically active steroids produced thereby.

The steroids of this invention include the 16a,l7a-acetal and ketal derivatives of 6halo-l6a,l7ot-dihydroxyprogesterones and ketones or aldehydes, wherein halo is either fluoro or chloro, and more particularly steroids of the general formula dd on wherein R is either chloro or fluoro in either the alpha or beta position; and P and Q are hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, or monocyclic heterocyclic alkyl; or together with the carbon atom to which they are joined P and Q is cycloalkyl or monocyclic heterocyclic.

The compounds of this invention are prepared, in accordance with the process of this invention, by interacting a steroid reactant of the general formula (lower alkylene) The 50:,6oc-6POXY derivatives are then treated with a haloride to yield the corresponding new 6,B-halo-5a-hydroxy derivatives of this invention having the formula (lower alkylene) /0 (lower alkylene) wherein R is as hereinbefore defined. The reaction is preferably conducted in an organic solvent system for both the steroid and halogenating reagent at any normal temperature, such as ambient temperature.

The ketal groups in the 3 and 20 positions and the cycloborate group in the 16, 17 position are then hydrolyzed by treatment with an acid, such as a mineral acid (e.g., sulfuric and perchloric acid) toyield the corresponding 6fi-halo-pregnane-5 l6a,l7a-triol-3,20-diones of this invention having the formula wherein R is as hereinbefore defined. Alternatively, the 6,8-halo-pregnene-5a,161;,l7m-triol-3,20-diones of this invention may be prepared from the cycloborates of Formula D by a two-step process comprising first the formation of the lower alkyl ester by treatment with a lower alkanol to form the compounds having the formula (lower alkyleue) /0 (lower alkylene) wherein R is as hereinbefore defined; and second, the

hydrolysis of the compound of Formula F, using a strong acid such as sulfuric or perchloric acid to yield the desired compounds of Formula E. The reaction to form Compound E is preferably conducted in an organic solvent for the steroid.

If an aldehyde or ketone is chosen as the solvent, then simultaneous hydrolysis and acetalization or ketalization occurs, thereby forming compounds having the formula wherein P, Q and R are as hereinafter defined.

If an inert organic solvent, such as a lower alkanol (e.g., methanol) is employed in the original hydrolysis, then the resulting 3,20-diketo steroids of Formula E can be acetalized or ketalized in the 16,17-position by treating with the desired aldehyde or ketone, preferably in the presence of an acid catalyst (e.g., perchloric acid, p-toluenesulfonic acid and hydrochloric acid), neutralizing the acid and recovering the acetal or ketal derivative of Formula G formed.

. In either event, among the suitable aldehydes and ketones may be mentioned aldehydes such as paraldehyde, propanal, chloral hydrate, trifluoroacetaldehyde hemiacetal, heptafluorobutanal ethyl hemiacetal and hexanal; di(lower alkyl) ketones, such as acetone, diethylketone, dibutylketone methylethylketone, and methylisobutylketone; halogenated di(lower alkyl)ketones, such as 1,1,1-trifluoroacetone; mono and dicycloalkyl ketones, such as cyclohexylmethyl ketone and dicyclopropyl ketone; cycloalkanones, such as cyclobutanone, cyclopentanone, cyclohexanone, suberone, and cyclodexanone; monocyclic aromatic aldehydes such as benzaldehyde,

'halobenzaldehydes (e.g., p-chlorobenzaldehyde and piiuorobenzaldehyde), lower alkoxy benzaldehydes (e.g., o-anisaldehyde), di(lower alkoxy) benzaldehydes (e.g., veratraldehyde), hydroxybenzaldehydes (e.g., salicyaldehyde), dihydroxybenzaldehydes (e.g., resorcylaldehyde), lower alkyl benzaldehydes (e.g., m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g., o,p dimethylbenzaldehyde), nitrobenzaldehydes,

acylamidobenzaldehydes (e.g., N-acetyl-anthranilaldehyde), and cyanobenzaldehydes; monocyclic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, B phenylpropionaldehyde, 'y phenylbutryaldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; and monocyclic heterocyclic lower alkanals, monocyclic aromatic ketones, such as acetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halophenyl lower alkyl ketones (e.g., p-chloroacetophenone and p-chloropropiophenone), (lower alkoxy)phenyl lower alkyl ketones (e.g., p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones, hydroxyphenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g., resacetophenone), (lower alkyl)phenyl lower alkyl ketones (e.g., methyl p-tolyl ketone), di(lower alkyl)phenyl lower alkyl ketones (o,p-xylyl methyl ketone), nitrophenyl lower alkyl ketones (e.g., pnitroacetophenone) acylamidophenyl lower alkyl ketones (e.g., acetylanilines), and cyanophenyl lower alkyl ketones; benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic aromatic lower alkanones, such as l-phenyl-3butanone and lphenyl-4-pentanone, and aromatically substituted derivatives thereof; monocyclic heterocyclic ketones such as 2-acetylfuran, Z-benzoyl furan, and Z-acetylthiophene; monocyclic heterocyclic lower alkanones; and monocyclic'heterocyclic ketones, such as alloxan.

The resulting l6,l7-cyclic acetal or ketal derivative of 6,3-(halo)pregnane-5oc,l6 x,l7a-triol-3,20-dione is then dehydrated by treatment with a dilute base (e.g., sodium hydroxide and sodium carbonate) in an inert solvent at ambient temperature or with an acid chloride (such as SOC1 and P001) in a tertiary base (such as pyridine) preferably in the cold (e.g., at 0 C.) to yield the corresponding 16,17-cyclic acetal or ketal derivative of 6,8-halo- 16a,l7a-dihydroxyprogesterone, final products of this invention having the general formula wherein P, Q and R are as hereinbefore defined.

To prepare the 6a-halo derivatives of this invention, the fi-halo group is inverted. This inversion can be accomplished by a number of methods. In accordance with one method, the 6/3-halo steroid is treated with hydrogen chloride in an organic medium. In accordance with another method, the 6B-halo steroids of Formula F and G are treated directly with hydrogen chloride in an organic medium such as acetic acid, to simultaneously invert the p-halo radical, hydrolyze any 3,20-ketal groups and form the 4,5-double bond thereby yielding the final products of this invention having the formula EXAMPLE I 6fl-fluoropregnane-5 (1,1 6 0a,] 7a-tri0l-3,20-di0ne 3,20-bisethylene ketal 1611,] 7 a-cycloborate (A) 5u,6a-ep0xypregnane-16a,] 7a-di0l-3,20-bisel hylene ketal and 5B,6fi-ep0xypregnane-16u,17a-di0l-3,20-biseth ylene keftzl.'To a solution of 4.35 grams (1O anillimoles) of 16a,l7a-dihydroxyprogesterone 3,20-bisethyl- -B, 1.99; F, 3.50; OCH

ene ketal [prepared as described in J.A.C.S., 78, 1909, (1956)] in 100 ml. of chloroform is added at over a period of ten minutes 40 ml. of a .5 N solution of monoperphthalic acid in ether. [The latter solution was prepared as described in The Journal of the American Chemical Society, vol. 77, page 3406 (1955).] The reaction mixture is allowed to remain at 0 for 16 hours following which it is poured with stirring into an ice cold solution of grams of sodium carbonate in 100 ml. of water. After separation of the layers, the chloroform solution is washed with water, dried over sodium sulfate and the-solvents removed in vacuo. The residual solid consists of a mixture of the 50,6aand 53,6,8epoxides. Separation of the two epoxides is achieved by recrystallization from acetone from which the a-epoxide separates first as the less soluble component. The pure a-epoxide after recrystallization from acetone has the following properties: M.P. about 260-262, 56 (c, .62 in chlf.).

Analysis-Calcd for C H O C, 66.64; H, 8.50. Found: C, 66.53; H, 8.46.

The SB-epoxide after recrystallization from acetone has the following properties: M.P. about 175-178, [061 -10.1 (c, .62 in chlf.). The yield of the a-epoxide is approximately 56% of theory, that of the B-epoxide approximately 20% of theory.

(B) Preparation of 6fl-fluor0pregnane-5aJ6a,17a-tri0l- 3,20-a'ione 3,20-bisethylene ketal I6a,]7a-cycl0borate.- To a clear solution of 1 g. of 5a,6a-epoxy-l6a,l7a-dihydroxyprogesterone 3,20-bisethylene ketal in 300 ml. of a 1:1 benzene:ether mixture, is added 7.5 ml. of freshly distilled borontrifluoride etherate. This mixture is stirred at room temperature for 3 hours, after which it is successively washed with distilled water, sodium bicarbonate solution and distilled water. The organic layer is then dried over sodium sulfate, filtered, evaporated to dryness and dried under vacuum. This material represents ylene ketal 160:,17ec-CYClObOIHt6.

broad 2.9 to 3.1 ,a

strong 6.62 and EXAMPLE II Methyl 6 ,B-fluoropregnane-S 04,1 6 04,1 7 a-triol-3,20-dione 3,20-bisethylene ketal 16a,17a-eycl0b0rate About 3 gins. of 6fi-fiuoropregnane-5a,16a,17o-triol-3, 20-dione 3,20-bisethylene ketal 160:,17wCYClOlJOI3t6 is dissolved in cold methanol and kept at room temperature for several hours, whereupon crystals (needles) separate out. These are filtered, Washed with cold methanol and dried under vacuum. About 3 g. of crystalline material is obtained. An analytical sample is prepared by slowly concentrating a cold methanol solution of the crystals at room temperature and washing the resulting crystals carefully with fresh methanol. It has the following properties: M .P. about 267 (dec.)

2.89 and 6.67 mu Analysis-Calcd for C H O BF: C, 59.78; H, 8.18; 11.44. Found: C, 60.26; H, 7.84; B, 1.81; F, 3.29; OCH 10.96; neut. equiv. 0.0

EXAMPLE III A solution of 1 g. of 6fi-fluoropregnane-5a,160;,1705- triol-3,20-dione 3,20-bisethylene ketal 16a,17a-cycloborate and 3.0 ml. of 8% sulfuric acid (w./v.) in 30 ml. of

.After neutralization was 3.00, 5.87 and 5.95 m .:,1;-, 290 m (6 400) Analysis- -Calcd for C H O F: C, 65.93; H, 8.27; F, 4.97. Found: C, 65.85; H, 8.35; F, 4.79.

EXAMPLE IV Preparation of 6,8-flu0ropregnane-5a,16a,Z7a-triol-3,20- dione by hydrolysis of methyl 6,8-fluoropregnane-5a, 16a,l7a-triol-3,20-dione 3,20-bisethylene ketal 16a,17acycloborate with sulfuric acid in methanol A solution of 1.3 g. of the compound of Example II and 4 ml. of 8% sulfuric acid (w./v.) in 40 ml. of methanol is heated to reflux for 15 minutes. The solution is diluted with water and concentrated in vacuo until most of the methanol is removed. The residual suspension is diluted with more water whereupon a heavy precipitate forms. This is filtered, washed with water and dried in vacuo. There is obtained about 770 mg. of pure 6fl-fiuoropregnane-5a,16a,17a triol 3,20 dione melting at about 230235. of theory). The infrared spectrum of this material is identical with that obtained in Example III. The overall yield from the oxido compound of Example I, part A via the borate ester is about 47%.

EXAMPLE V Preparation of 6B-flu0r0pregnane-5aJ 60:,1711 triol 3,20- dione 16a,]7oc-ZCl0nid8 by the aceto'nation of 6,8-fluoropregnane-SaJ 6 05,1 7 a-triol-3,2 O-dione To a solution of 212 mg. of 6,8-fluoropregnane-5a,16a, 17u-triol-3,20-dione in 20 ml. of acetone, is added 0.02 ml. of 70% perchloric acid and the mixture allowed to remain at room temperature With stirring for 2 hours. with sodium bicarbonate solution and addition of water. the bulk of the acetone is removed in vacuo. The resulting precipitate is filtered, Washed with water and dried in vacuo. There is obtained about 206 mg. of the acetonide melting at about 259-264 C. Re-

crystallization from acetone-hexane furnishes the pure 6fl-fluoropregnane-5m16a,17a-triol 3,20 dione 16a,17ocacetonide having the following properties: M.P. about 268-271"; [a] +55 (c, .67 in chlf.);

A 2.94, 5.85, 5.91 mu; A33 no selective absorption EXAMPLE VI Preparation 0 6,8-fluoropregnane-5 a,1 6a,] 70: triol 3,20-

dione ]6a,17a-acetonide by simultaneous hydrolysis and acetonation of methyl 66 fluoropregntme 504,161,170:- tri0l-3,20-di0ne-3,20-bis-ethyZene ketal 160:,17u cycloborate To a solution of 240 mg. of the cycloborate of Example II in 25 ml. acetone, is added 0.025 ml. of 70% perchloric acid, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is then neutralized with dilute sodium bicarbonate, diluted with water and the bulk of the acetone removed in vacuo. The resulting precipitate is filtered, washed well with water and dried in vacuo. There is obtained about mg. of crude acetonide melting at about 220-225. Several recrystallizations from acetone-hexane raise the melting point to about 250. An ultraviolet spectrum of the mother liquor shows the presence of a small amount (10%) of a A -3- keto compound, while an infrared spectrum of the crystalline material shows it to be the desired pure acetonide.

EXAMPLE VII Preparation of acetophenone derivative of 6,8-flnoropregnane-5a,16a,1 7atriol-3,20-dione To a suspension of 100 mg. of 6fifi110r05a,16oc,17octrihydroxypregnane-3,20-dione in 2 ml. of freshly distilled acetophenone, is added with stirring 0.01 ml. of 70% perchloric acid. The suspension clears within 5 minutes, and the reaction is allowed to proceed for an additional 30 minutes. This mixture is neutralized with dilute sodium bicarbonate solution; and after the addition of water, extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate, filtered and evaporated to dryness in a high vacuum to remove residual acetophenone. The crude product shows an ultraviolet absorption spectrum at 234 m with a molar extinction co-efiicient of 4,000 indicating partial dehydration to the A -3-ketone. It is used in the process of Example IX, without further purification.

EXAMPLE VIII Preparation of 6fi-flaoro-16a,]7a-dihydroxypr0gester0ne- 16DL,170-(1C2f01lid by dehydration of 6,8-fluorpregna nea-16a-17a-triol-3,20-dione 16a,1 7a-acet0nide with sodium hydroxide in ethanol To a solution of 140 mg. of ofl-fluoropregnane -5a,l6a, 17a-trio1-3,20-dione 16a,17oc-8.Ce'tOIlidC in 30 ml. of 95% ethanol is added 1.5 ml. of 0.1 N sodium hydroxide. The mixture is allowed to stand at room temperature for 18 hours, following which it is neutralized with acetic acid, diluted with water and concentrated in vacuo. After cooling, the crystals are separated by filtration, washed thoroughly with water and dried in vacuo. There is obtained about 108 mg. of 6e-fluoro -16a,17a dihydroxyprogesterone 16a,17a-acetonide melting at 227230 C.

Crystallization from methanol furnishes a pure sample with the following properties: M.P. about 237-238"; [a] |43.3 (c, .90 in.chlf.);

A313,, 232 m (e -11,700); Ami? 5.85, 5.95, 6.20 m

Analysis.Calcd for C H O F: C, 71.26; H, 8.22; F, 4.70. Found: C, 71.29; H, 8.13; F, 4.79.

EXAMPLE IX Preparation of acetophenone derivative of 6p-flnoro-16a,

17a-dihydroxyprogesterone by dehydration of the acetophenone derivative of 613 fluoropregnane 5a,16ot,17atriol-3,20-di0ne with sodium hydroxide A solution of the acetophenone derivative of 6fl-fluoropregnane 5oc,l6ot,17ot triol 3,20 dione obtained as described in Example VII in 10 ml. of 95% ethanol and 1 ml. 0.1 N NaOH is treated as described in Example VIII. The resulting dehydration product is purified by chromatography on alumina to yield the desired acetophenone' derivative of 16a,17a-dihydroxyprogesterone.

EXAMPLE X Preparation of 6a-fla0ro-16a,]7a-dihydroxyprogesterone l6a,17a acetonide by epimerization of 6,8 fluoro-16a, 17a-dihydroxyprogesterone 16a,17a-acet0nide Analysis.Found: C, 71.37; H, 8.22; F, 4.71. Calcd: C, 71.25; H, 8.22; F, 4.70.

EXAMPLE XI Preparation of the acetophenone derivative of 6a-fluoro- 16a,17a-dihydroxyprogesterone by epimerization of the acetophenone derivative of 6,8-fluoro-16ot,17a-dihydroxyprogesterone Following the procedure of Example X, the 6,8-fiuoroacetophenone derivative is treated with hydrogen chloride gas in glacial acetic acid and the reaction mixture allowed to stand. The reaction mixture is diluted with water, extracted with chloroform, etc. to give a residue which is purified by chromatography on neutral alumina. Elution of the column yields the desired 6a-fluoro-epimer.

EXAMPLE XII Preparation of 6a-flu0r0-160:,17a-dihydroxyprogesterone- 16a, 17a-acet0nide by simultaneous dehydration and epimerization of 6fl-fluoropregnane-5 (1,1 6a,] 7oc-tri0l-3, ZO-dione 16,17a-acet0nide Following exactly the procedure of Example X, but

substituting 6B fluoropregnane 5a,16a,17a triol -3,20-

dione-16a,17a-acetonide for the 6,6-fluoro-16a,17a-dihydroxyprogesterone 16a, 17a acetonide, '600 fluoro- 16a,17a-dihydroxyprogesterone-16a,17a-acetonide of the same properties is formed.

EXAMPLE XIII Preparation of 6 ,B-chloropregnane-S 11,1 6 a,] 7a-triol-3- 20-di0ne-3,20-bisethylene ketal 16a,17a-cyel0b0rate Following the procedure of Example IB, except for the substitution of boron trichloride, for the boron trifiuoride, 6,6 chloropregnane 5a,16a,17a triol 3,20 dione 3,20-bisethylene ketal 16a,17a-cycloborate is formed.

EXAMPLE XIV Preparation of 6,8-chl0ropregnane-5a,16a,I7a-triol-3,20- dione EXAMPLE XV Preparation of 6B-chl0ropregnane-5a,1 6 oc,1 7 ot-tliOl-3 ,20 dione 16a,17oc-acetonide The product of Example XIV is acetonated in accordance with the procedure of Example V by treatment with a mixture of acetone and 70% perchloric acid to yield the desired 6,8-chloropregnane 5a,l6a,l7a-triol-3,20-dione 16a,17a-acetonide.

EXAMPLE XVI dihydroxyprogesterone 16a,17a acetonide. 6/3 chloro- 16a,17a dihydroxryprogesterone 1604,170: acetonide can be prepared from the same starting material by treatment with 0.005 N sodium hydroxide in accordance with the procedure of Example VIII.

EXAMPLE XVII To a suspension of 100 mg. of 5a,16a,17a-trihydroxy- 6/3-fluoropregnane-3,ZO-dione in 15 ml. of methylethylketone is added 0.05 ml. of 72% perchloric acid, and the mixture stirred at room temperature for two hours. The resulting solution is neutralized with sodium bicarbonate solution and after addition of water the methylethylketone is evaporated in vacuo. The resulting crystals are filtered, washed with Water and dried in vacuo. Recrystallization from acetone-hexane gives the pure isobutylidene derivative.

EXAMPLE XVIII 1 6a,] 7a- 4 '-m'ethyl-2 '-p entylidene) 5a,16a,1 7a-trihyairway-6p-chloropregnane-3,20-diane To a suspension of 100 mg. of 5a,16a,17a-trihydroxy- 6fi-chloropregnane-3,20-dione in 15 ml. of methylisobutylketone, is added 0.05 ml. of 72% perchloric acid. The mixture is stirred at room temperature for 6 hours and the resulting solution extracted With dilute sodium bicarbonate solution, Washed with water, the organic phase dried over sodium sulfate and the solvent evaporated in vacuo. Recrystallization of the resulting crystals from acetone-hexane gives the pure isohexylidene derivative.

EXAMPLE XIX A suspension of 200 mg. of 5a,16a,17a-trihydroxy-6/3- fiuoropregnane-3,20-dione in 15 ml. of redistilled cyclohexanone is treated for tWo hours as described in Example XVIII.

EXAMPLE XX 16a,17a-(3'pentylidene)5a,16a,17a-trihydroxy-6flpregnane-3,20-dine A suspension of 200 mg. of a,l6a,l7a-trihydroxy-6/3 fluoropregnane-3,20-dione in 30 ml. of diethylketone is treated for four hours as described in Example XVIII.

EXAMPLE XXI To a suspension of 200 mg. 5a,16a,17a-trihydroxy-6flfiuoropregnane-3,20-dione in ml. of freshly distilled paraldehyde, is added 0.05 ml. of 72% perchloric acid and the mixture agitated for 3.5 hours at room temperature. The resulting solution is extracted With dilute bicarbonate and Water, dried, and the excess paraldehyde removed in vacuo. The residual material represents 16a,17a ethylidene 5a,16oz,17a trihydroxy 6p fluoropregnane-3,20-dione.

EXAMPLE XXII 1 6 a,] 7 oc-C'hlOrdl derivative of 5 0a,] 6 C1,] 7a-trihydroxy-6B- ch loropregnane-3 ,20-di0ne A suspension of 500 mg. of 501,1611,17ot-iflhYdl07QY-6fi' ch1oropregnane-3,20-dione and 4 gm. of chloral hydrate in 20 ml. of dioxane is agitated at room temperature for 24 hours. The mixture is filtered, neutralized with aqueous sodium bicarbonate and extracted with chloroform. The chloroformdioxane phase is dried over sodium sulfate, the solvent removed in vacuo and the residual chloral derivative crystallized from methanol.

1 0 EXAMPLE XXIII Following the procedure of Example XXH, but replacing the chloral hydrate used in that example by a mix ture of S ml. of dioxane and 5 ml. of 1,1,1-trifluoroacetone there is obtained the trifluoroisopropylidene derivative.

EXAMPLE XXIV Benzaldehya'e derivative 0 5a,] 6a,] 7 a-trihydroxy-6flflaoropregnane-3,20-dione To a suspension of mg. of 5a,16a,17a-trihydroxy- 6,8-fiuoropregnane-3,ZO-dione in 15 ml. of benzaldehyde, is added 0.05 ml. of 72% perchloric acid. The mixture is treated as in Example XXII and results in the formation of the benzaldehyde derivative of 5a, 16a,17a-trihydroxy- 6 3-fluoropregnane-3,20-dione.

EXAMPLE XXV F urfural derivative of 5 0a,] 6 a, l 7a-trihydroxy-6fl-flworo pregnane-3,20-dione Treatment of 50,16a,17a-trihydroxy-6,8-fluoropregnane- 3,20-dione with furfural in the presence of perchloric acid according to the procedure of Example XXII results in the formation of the furfura-l derivative of 5a,16oc,17- trihydroxy-6 8-fiuoropregnane-3,20-dione.

EXAMPLE XXVI Dicyclopropyl ketone derivative of 5a,16a,17a-Zrihydr0xy- 6B-chl0r0pregnane-3,20-dione Following the procedure of Example XXII, but replacing the trifluoroacet-one by dicyclopropyl ketone, there is obtained the dicyclopropyl derivative of 5a,16ot,17atrihydroxy-6fl-chloropregnane-3,20-dione.

EXAMPLE XXVII Preparation of 1604,] 70c- (2-butyliden.e)16a,17ocdihydroxy-6fl-fluoroprogester'one A solution of the product of Example XVII in ethanol is treated with sodium hydroxide in accordance with the procedure of Example VIII to yield as the final product 16oc,17oe (2' butylidene) 1611,1711: dihydroxy 6,8 fluoroprogesterone.

The 6oz-fil10l0 analogue is readily obtained by treating the same starting material in accordance with the epimer zation procedure of Example X.

EXAMPLE XXVIII Preparation of J 60:,170: (4-methyl-2'-p'entylidene) 6fl-chl0ro-1 6 0a,] 7 a-dihydroxy progesterone The product of Example XVIII is dehydrated in accordance With the dehydration procedure of Example VIII to yield the desired product.

The 6a-chloro analogue is readily obtained by subjecting the same starting material to the epirnerization procedure described in Example X.

EXAMPLE XXIX Preparation of 16a,]7u-cycl0hexylidene]60:,1704- dihydroxy-6fi-flaor0pr0gesterone The corresponding 602-111101'0 analogue is obtained by subjecting the final product of Example )Q( to the epimerization procedure'of Example X. p

In the same manner as in Example XXX, the products of Examples XXI through XXVI are converted to their dehydrated and epimerized analogues having the group of the 6-position in the B and on configuration by treatment respectively in accordance with the procedures of Examples VIII and X.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A steroid of the general formula lower alkylene) 12 wherein Ris a halogen selected from the group consisting of fluorine and chlorine.

2. 5a,16a,17a-trihydroxy-6B-fiuoropregnane 3,2-O-bisethylene ketal. References Cited UNITED STATES PATENTS 2,838,496 6/1958 Babcock et a1. 260239.55 2,838,528 6/1958 Campbell et a1. 260-397.3 2,838,540 6/1958 Campbell et a1. 260397.45 10 2,881,168 4/1959 Spero et al 260-23955 2,941,997 6/1960 Fried 260-23955 3,021,347 2/1962 Allen et al 260397.45

OTHER REFERENCES 15 Cooley et al., J. Chem. Soc. (London), December 1955, pages 4373-4377 (pages 4374 and 4376 necessary). Fried et al., J. Am. Chem. Soc., vol. '80 (May 5, 1958),

pages 2338 and 2339.

0 Mills et al., I. Am. Chem. Soc., vol. 81 (Mar. 5, 1959);

ELBERT L. ROBERTS, Primary Examiner.

L. H. GASTON, M. LIEBMAN, LEWIS GOTTS,

Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,541,525 September 12, 1967 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 55, after formula "B." insert with a peracid, such as perbenzoic acid, monoperphthalic acld and peracetic acid, to yield the 501.,60t-POXY derlvatlves having the formula column 3, line 18, for "hereinafter" read hereinbefore column 8, line 1, for "solutiton" read solution Signed and sealed this 1st day of October 1968.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, Jr.

Attesting Officer 

1. A STEROID OF THE GENERAL FORMULA 